2-148178611-A-C

Position:

• chr2-148178611-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378120.1(MBD5):​c.-924-89A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 388,598 control chromosomes in the GnomAD database, including 25,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8363 hom., cov: 32)
  • Exomes 𝑓: 0.38 (17624 hom.)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0520

Genes affected

MBD5 (HGNC:20444): (methyl-CpG binding domain protein 5) This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

MBD5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-148178611-A-C is Benign according to our data. Variant chr2-148178611-A-C is described in ClinVar as [Benign]. Clinvar id is 1262738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-924-89A>C		intron_variant		ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-924-89A>C		intron_variant			NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46862 AN: 152000 Hom.: 8368 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.335

GnomAD4 exome AF: 0.381 AC: 90037 AN: 236480 Hom.: 17624 AF XY: 0.382 AC XY: 45877 AN XY: 120110

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.441

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.385

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.308 AC: 46866 AN: 152118 Hom.: 8363 Cov.: 32 AF XY: 0.307 AC XY: 22806 AN XY: 74360

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.429

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.389

Gnomad4 OTH AF: 0.334

Alfa AF: 0.342 Hom.: 1215

Bravo AF: 0.304

Asia WGS AF: 0.316 AC: 1095 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12465610; hg19: chr2-148936180; COSMIC: COSV69486586; COSMIC: COSV69486586;